AB0432 EFAVALEUKIN ALFA, A NOVEL IL-2 MUTEIN, SELECTIVELY EXPANDS REGULATORY T CELLS IN PATIENTS WITH SLE: FINAL RESULTS OF A PHASE 1B MULTIPLE ASCENDING DOSE STUDY
Authors: N. Tchao, N. Sarkar, X. Hu, R. Zhang, C. Milmont, Y. Shi Jin, V. Chow, M. Kroenke, K. Gorski, R. Furie, A. Kivitz, S. Cohen
Journal: Annals of the Rheumatic Diseases (2022)

Background Defects in regulatory T cell (Treg) number and function are associated with autoimmune diseases including SLE. Interleukin (IL)-2 is essential for the development and suppressive function of Treg, and therapies that exploit the ability of IL-2 to expand Treg have shown disease-modifying potential in SLE 1 . However, low-dose IL-2 has a short half-life and narrow selectivity for Treg over conventional CD4+ T cells (Tcon) and natural killer (NK) cells. Efavaleukin alfa is an IL-2 mutein Fc fusion protein; an introduced mutation decreases binding to IL-2Rβ and increases dependence on IL-2Rα (CD25). This preferential binding to the high-affinity IL-2R, constitutively expressed at high levels on Treg, leads to increased cell surface retention and sustained Treg signaling compared with recombinant IL-2. In healthy subjects, a single dose of efavaleukin alfa was well tolerated and led to robust and selective Treg expansion 2 . Objectives This final analysis of a phase 1b, double-blind, placebo-controlled, multiple ascending dose study ( NCT03451422 ) reports the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic effects of efavaleukin alfa in patients with SLE. Methods The study included five ascending dose cohorts (cohort 1=lowest dose; cohort 5=highest dose). A total of 35 patients with SLE (age 24–71 years; 85.7% female; SLE diagnosed using SLICC or ACR criteria with ANA ≥1:80 and/or elevated anti-dsDNA antibodies) were randomized to receive efavaleukin alfa or placebo (5:2 ratio for cohorts 1–3; 3:1 ratio for cohorts 4–5) subcutaneously every 2 weeks (Q2W; cohorts 1, 2, 4, and 5) or every week (QW; cohort 3) in addition to standard of care therapy for a total of 12 weeks, with 6 weeks of follow-up. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Additional endpoints included serum PK of efavaleukin alfa and changes in numbers of Treg, CD4+ Tcon, CD8+ T cells, and NK cells in peripheral blood. Results The most commonly reported TEAEs (occurring in ≥25% of efavaleukin alfa-treated subjects) included non-serious, mild or moderate (grade 1–2) injection site reactions. No grade 4 TEAEs or deaths occurred. Two serious AEs were reported in efavaleukin alfa-treated subjects: one event of syncope (grade 3) was observed in cohort 2 and was not considered related to treatment, and one case of eosinophilia (grade 2) was observed in cohort 5 and was considered related to treatment. Efavaleukin alfa PK was generally linear and dose-proportional, with a terminal half-life ranging from 18–30 hours. Peak Foxp3+ Treg expansion was observed at 8 days post-dose, and the magnitude of the peak was generally sustained after multiple QW or Q2W doses. The mean peak increases in Foxp3+ Treg were 14.8-, 17.4-, 5.7-, 2.4-, and 1.1-fold above baseline for efavaleukin alfa Q2W dosing cohorts 5, 4, 2, and 1 and placebo, respectively. At the final study assessment (42 days after the last dose), the mean Treg count was 1.3-fold above baseline (95% CI, 0.9–1.9). Treatment with efavaleukin alfa also expanded CD25 bright Treg (peak 53.8-fold change) and CD31+ recent thymic emigrant (RTE), naïve, and memory Treg subsets. At the highest dose (cohort 5), low-level increases in numbers of CD4+ Tcon (peak 2.3-fold), CD8+ T cells (peak 2.1-fold), and NK cells (peak 2.9-fold) were observed. Conclusion Multiple ascending doses of efavaleukin alfa were safe and well tolerated and led to selective and prolonged Treg expansion in SLE patients. Results at the highest dose suggest a plateau in Treg expansion with low-level increases in other IL-2–responsive cells, although interpretation is limited due to small subject numbers. The highest tested dose may be outside the therapeutic window and thus will not be assessed in phase 2 clinical studies. These findings confirm and extend previous results in healthy subjects and support the ongoing phase 2b adaptive randomized controlled trial in patients with SLE. References [1]Humrich J. Arthritis Rheumatol. 2016;68 (suppl 10); 2 Tchao N. Blood. 2017;130 (suppl 1). Acknowledgements Funding: Amgen Inc Disclosure of Interests Nadia Tchao Shareholder of: Amgen Inc., Employee of: Amgen Inc., Nandita Sarkar Shareholder of: Amgen Inc., Employee of: Amgen Inc., Xuguang Hu Shareholder of: Amgen Inc., Employee of: Amgen Inc., Rong Zhang Shareholder of: Amgen Inc., Employee of: Amgen Inc., Cassandra Milmont Shareholder of: Amgen Inc., Employee of: Amgen Inc., Yan Shi Jin Shareholder of: Amgen Inc., Employee of: Amgen Inc., Vincent Chow Shareholder of: Amgen Inc., Employee of: Amgen Inc., Mark Kroenke Shareholder of: Amgen Inc., Employee of: Amgen Inc., Kevin Gorski Shareholder of: Amgen Inc., Employee of: Amgen Inc., Richard Furie Consultant of: Amgen Inc, Grant/research support from: Amgen Inc, Alan Kivitz Shareholder of: Amgen Inc., Gilead, GlaxoSmithKline, Novartis, Pfizer, and Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, GSK, Horizon, Lilly, Merck, Novartis, Pfizer, Sanofi, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Gilead, Janssen, Pfizer, Sanofi, and Sun Pharma, Stanley Cohen Consultant of: Amgen Inc., AbbVie, Eli Lilly, Pfizer, Genentech, and Gilead, Grant/research support from: Amgen Inc., AbbVie, Eli Lilly, Pfizer, Genentech, and Gilead